Use of a novel genetic mouse model to investigate the role of folate in colitis-associated colon cancer.
Inflammatory bowel disease (IBD) patients are at high risk for developing folate deficiency and colon cancer. Since it is difficult to study the subtle global and gene-specific epigenetic mechanisms involved in folate-mediated tumor initiation and promotion, we have generated genetically modified mouse models by targeting the reduced folate carrier (RFC1) and folate-binding protein (Folbp1) genes. The transgenic mice were fed semi-purified diets for 8 weeks containing either normal (2 mg) or deficient (0.1 mg folate/kg diet) levels of folate. Compound heterozygous mice (Folbp1(+/-); RFC1(+/-)) fed an adequate folate diet exhibited a reduction in plasma folate concentrations compared to heterozygous (Folbp1(+/-)) and littermate wild-type mice (P<.05). In contrast, no differences were observed in colonic mucosa. Consumption of a low folate diet significantly reduced (three- to fourfold) plasma and tissue folate levels in all animal models, although plasma homocysteine levels were not altered. In order to elucidate the relationship between folate status and inflammation-associated colon cancer, animals were injected with azoxymethane followed by dextran sodium sulphate treatment in the drinking water. Mice were fed a normal folate diet and were terminated 5 weeks after carcinogen injection. The number of high multiplicity aberrant crypt foci per centimeter of colon was significantly elevated (P<.05) in compound Folbp1(+/-); RFC1(+/-) (3.5+/-0.4) mice as compared to Folbp1(+/-) (1.9+/-0.3) and wild-type control mice (1.1+/-0.1). These data demonstrate that the ablation of two receptor/carrier-mediated pathways for folate transport increases the risk for developing inflammation-associated colon cancer.
Chapkin
Robert S
RS
Faculty of Nutrition, Texas A&M University, College Station, TX 77843-2253, USA. r-chapkin@tamu.edu
Kamen
Barton A
BA
Callaway
Evelyn S
ES
Davidson
Laurie A
LA
George
Nysia I
NI
Wang
Naisyin
N
Lupton
Joanne R
JR
Finnell
Richard H
RH
D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D015415:Biomarkers; D001923:Brain Chemistry; D002273:Carcinogens / Q000633:toxicity; D002352:Carrier Proteins / Q000235:genetics*; D003092:Colitis / Q000150:complications*; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D005494:Folic Acid Deficiency / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D005526:Food, Formulated; D006579:Heterozygote; D006710:Homocysteine / Q000097:blood; D007413:Intestinal Mucosa / Q000737:chemistry / Q000473:pathology; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009752:Nutritional Status; D011230:Precancerous Conditions / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface / Q000235:genetics*; D058978:Reduced Folate Carrier Protein
D015415:Biomarkers; D002273:Carcinogens; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D026901:Membrane Transport Proteins; D011956:Receptors, Cell Surface; D058978:Reduced Folate Carrier Protein; C548700:Slc19a1 protein, mouse; D006710:Homocysteine; D016264:Dextran Sulfate; D005492:Folic Acid; D001397:Azoxymethane